Fibromyalgia Drug Milnacipran Successful in Phase II Study

Cypress Bioscience Inc. announced on March 21, 2003, that its lead product candidate, milnacipran, was shown to statistically improve a number of primary and secondary hallmark symptoms of fibromyalgia syndrome (FMS), including occurrence/intensity of pain and overall well-being.

It is estimated that as many as five million to 11 million Americans have Fibromyalgia Syndrome (FMS), one of a number of centralized pain disorders known as Functional Somatic Syndromes (FSS).

Milnacipran-treated patients showed statistically significant overall improvement and improvement in pain intensity, according to results presented at the 22nd Annual Scientific Meeting of the American Pain Society in a symposium entitled, “Fibromyalgia: Current Understanding and Future Directions.” The results were presented by Daniel Clauw, M.D., Professor of Medicine, Division of Rheumatology; Director, Center for Advancement of Clinical Research; and Director, Chronic Pain and Fatigue Research Program at the University of Michigan, and Chairman of Cypress’ Rheumatology Advisory Board.

“We have made great strides in learning more about the pathophysiology of fibromyalgia syndrome and the role of norepinephrine and serotonin in mediating central pain, which has helped point us in the direction of what could be the first therapy specifically developed to treat people with this common disorder,” said Dr. Daniel Clauw. “It is impressive to see such a significant improvement in symptoms in this patient population.”

The double-blind, placebo-controlled, flexible dose escalation monotherapy trial is the first to evaluate the safety and efficacy of milnacipran in treating patients with FMS. There are currently no treatments approved by the U.S. Food and Drug Administration (FDA) to treat fibromyalgia.

Positive Clinical Result Seen in Improvement of Pain

Milnacipran-treated patients randomized to the twice-daily dosing group (BID) showed statistically significant improvement in pain, compared to those who received placebo. Further, 37 percent reported at least a 50 percent reduction in the intensity of their pain, compared to just 14 percent of placebo patients, a statistically significant difference (p=0.0395, intent to treat analysis).

Milnacipran BID was also statistically superior to placebo treatment on multiple secondary pain outcome measures including the pain scales from the fibromyalgia impact questionnaire (FIQ), the McGill pain questionnaire, and a 24 hour recall visual analogue pain scale.

Positive Clinical Result Seen in Percentage of Patients Feeling Better

Seventy-five percent of all milnacipran-treated patients reported overall improvement, compared to 38 percent in the placebo group (p=0.004).

Milnacipran patients also reported significant improvement in fatigue on the FIQ fatigue scale.

A total of 125 patients enrolled in the trial and were randomized to receive either placebo or milnacipran either once or twice a day for four weeks of dose escalation, followed by eight weeks of constant dose. The study evaluated the efficacy and safety of milnacipran for the treatment of pain and associated symptoms such as fatigue, depressed mood and ability to sleep.

Eighty-four percent of all milnacipran patients escalated to the highest dose with no tolerability issues. The most common dose-related side effect reported by patients was nausea, particularly early in the study. Most adverse events were mild to moderate in intensity and transient in duration.

“Attempts to treat the complex pain of fibromyalgia with existing medications have met with limited success,” noted Jay D. Kranzler, MD, PhD, Chairman of the Board and Chief Executive Officer of Cypress Bioscience Inc. “Based on these results, milnacipran appears to have the potential to relieve several of the symptoms associated with fibromyalgia, and perhaps other related Functional Somatic Syndromes.”

Milnacipran is the first in a new class of oral therapeutics known as Norepinephrine Serotonin Reuptake Inhibitors (NSRIs) that decrease the uptake of both norepinephrine and serotonin, two neurotransmitters known to play an essential role in regulating pain and mood.

Assuming a positive outcome of upcoming discussions with the FDA regarding next steps, the company plans to initiate the necessary Phase III trials to further evaluate milnacipran as a treatment for Fibromyalgia Syndrome.

Chronic pain conditions such as fibromyalgia have a number of overlapping clinical characteristics with depression. It is also known that chronic pain leads to depression and, as well, depression can precede chronic pain.

Furthermore, it has been observed that mood, personality and substance abuse disorders are common in patients who suffer from acute pain and that pain is the somatic symptom that most highly correlates with, and is most predictive of, generalized anxiety disorder and major depressive disorder. However, while serotonin levels are particularly important in the treatment of depression, norepinephrine is more important in the treatment of central pain. Thus, NSRIs, that affect both neurotransmitter systems but with a preference for norepinephrine, may be beneficial due to this simultaneous neurotransmitter mediation, according to research previously reported by Dr. Clauw at the annual meeting of the Society for Psychosomatic Medicine.

“Previous studies have suggested that for depression, drugs that act on serotonin or norepinephrine alone are equally effective. In contrast, for pain, mixed serotonin/norepinephrine drugs, and particularly those with a norepinephrine preference, appear to be more effective than drugs that act on either neurotransmitter alone. The results of this fibromyalgia study are entirely consistent with these previous findings,” Dr. Clauw said.

Fibromyalgia is characterized by a number of chronic, debilitating symptoms such as pain, fatigue and inability to sleep. It is associated with other functional somatic syndromes such as irritable bowel syndrome (IBS), chronic headache, temporomandibular joint dysfunction syndrome (TMJ) and multiple chemical sensitivity syndrome.

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